1. Field of the Invention
The present invention relates to systems for targeting pharmacologically active substances to the central nervous system of a mammal. Particularly, the present invention concerns nanoparticulate drug targeting systems which are capable of crossing the blood-brain barrier of a mammal. More particularly, the present invention pertains to drug-loaded nanoparticles on the basis of polylactides and/or polylactide-coglycolides, to methods for producing drug-loaded nanoparticles on the basis of polylactides and/or polylactide-coglycolides, and to the use of drug-loaded nanoparticles on the basis of polylactides and/or polylactide-coglycolides for the treatment of diseases or disorders of the central nervous system, in particular to the treatment of neuronal cancer.
2. Description of the Prior Art
Diseases and disorders of the central nervous system (CNS) may be treated by administering drugs that have an impact on nervous system function. These drugs are usually given to a patient in need thereof by conventional oral administration or by injection. Unfortunately, many drugs such as adenosine, β-endorphine, synthetic analogs of endogenous peptides, excitatory and inhibitory amino acids and trophic factors do not pass the blood-brain barrier at all or only in amounts insufficient to be therapeutically efficient. Such drugs are only therapeutically effective when administered directly into the brain, for instance by direct CNS infusion.
As an alternative to direct CNS infusion, U.S. Pat. No. 6,117,454 suggests a method for transmitting pharmaceutically active substances across the blood-brain barrier of a mammal, wherein nanoparticles shall be used to target drugs or diagnostic agents to the CNS by crossing the blood-brain barrier. Pursuant to U.S. Pat. No. 6,117,454, a drug is added during or after polymerization of suitable monomers such as butyl cyanoacrylate to be either incorporated into or adsorbed onto the surface of the resulting poly-butyl cyanoacrylate nanoparticles. These nanoparticle-drug complexes are said to be able to cross the blood-brain barrier and to target the drug to the CNS if they are coated with an appropriate surfactant. Polyoxyethylene 20 sorbitan monolaurate (TWEEN® 20), polyoxyethylene 20 sorbitan monopalmitate (TWEEN® 40), polyoxyethylene 20 sorbitan monostearate (TWEEN® 60), polyoxyethylene 20 sorbitan monooleate (TWEEN® 80), and mixtures thereof are claimed to be appropriate surfactants that enable the drug-loaded poly-butyl cyanoacrylate nanoparticles to cross the blood-brain barrier.
It is proposed in this document that basically any drug could be incorporated into or bound to the surfactant-coated nanoparticles and be delivered to the brain without the need to alter the structure of the drug. Hence, it appears that U.S. Pat. No. 6,117,454 provides the first universal method of targeting a drug to the CNS by crossing the blood-brain barrier.
Concerns about the probability of toxic side effects of the surfactants used to coat the resulting poly-butyl cyanoacrylate nanoparticles and the desire to simplify the production process of drug-loaded nanoparticles led to the development of a simplified and potentially less toxic method of nanoparticle fabrication as disclosed in WO 98/56361.
WO 98/56361 teaches that surfactants are no longer required if nanoparticles are prepared by using Dextran 12.000 or polysorbate 85 (polyoxyethylene 20 sorbitan trioleate; TWEEN® 85) as stabilizers during the polymerization of butylcyanoacrylate monomers. It was shown that dalargin being adsorbed onto the stabilized polybutylcyanoacrylate nanoparticles can pass the blood-brain barrier, and that amitriptyline being adsorbed to polysorbate 85-stabilized nanoparticles accumulates to higher concentrations in the brain than amitriptyline as such.
However, there is still a demand for alternative systems of drug-loaded nanoparticles for targeting drugs to the CNS of a mammal across the blood-brain barrier, in order to improve one or more of efficacy, specificity, toxicity, and simplicity of preparation.